Viruses in the male genital tract and their effects on the reproductive system. N Dejucq, B Jegou. Microbiol Mol Biol Rev 2001 Jun;65(2):208-231. "In addition to providing an exhaustive account of the data available in these domains, this review focuses attention on the fact that the interface between endocrinology and virology has so far been poorly explored, particularly when major health, social and economical problems are posed."Dejoucq - Microbiol Mol Biol Rev 2001 abstract / PubMed
Meta-analysis of measures of sexual activity and prostate cancer. LK
Dennis, DV Dawson. Epidemiology 2002 Jan;13(1):72-79. "The data suggest
an elevated relative risk (RR) of prostate cancer among men with a
history of sexually transmitted infections. This was observed with both
random- and fixed-effects models (RR = 1.4; 95% CI = 1.2-1.7; N = 17
studies; heterogeneity P = 0.14), especially for syphilis (RR = 2.3;
95% CI = 1.3-3.9; N = 6; heterogeneity P = 0.47). Risk of prostate
cancer is also associated with increasing frequency of sexual activity
(RR = 1.2 for an increase of three times per week; 95% CI = 1.1-1.3; N
= 12). However, these studies are heterogeneous (P < 0.001).
Increasing number of sexual partners is also associated with prostate
cancer (RR = 1.2 for an increase of 20 partners; 95% CI = 1.1-1.3; N =
16; heterogeneity P = 0.11). The data do not support associations with
multiple marriages, age at first intercourse, or age at first marriage.
These results indicate an association between prostate cancer and
sexually transmitted infections, suggesting that infections may
represent one mechanism through which prostate cancer develops."
Demonstration of Epstein-Barr virus in carcinomas of various sites.
S Grinstein, MV Preciado, P Gattuso, PA Chabay, WH Warren, E De Matteo,
VE Gould. Cancer Res 2002 Sep 1;62(17):4876-4878. "Seven of 19
carcinomas showed strong EBV reactions in 5–30% of neoplastic nuclei.
These cases included all grades of the Gleason classification ranging
from well-differentiated adenocarcinomas (Fig. 1i) to hypernephroid and
solid tumors. One of 7 carcinomas included foci of high-grade PIN,
where convincing EBV reactive nuclei were seen in both basal and
luminal cells (Fig. 1j) . All prostate carcinoma samples included foci
of benign glandular hyperplasia, 3 of which showed sporadic positive
nuclei; 10 normal prostate samples were negative. CD21 was not detected
in epithelial cells. Our findings of EBV in prostatic carcinomas are
entirely new. In these cases, the presence and possibility of EBV
appeared unrelated to the degree of neoplastic differentiation because
it was found in the entire range of tumors from those composed of
regular glands to poorly differentiated and hypernephroid carcinomas.
Interestingly, an architecturally and cytologically distorted carcinoma
removed after androgen deprivation therapy showed abundant EBV-reactive
cells. Also, in a single case of carcinoma, foci of high-grade PIN,
acknowledged to be a precancerous proliferation, showed EBV
immunostaining. This apparently low incidence may simply reflect the
fact that the blocks containing carcinoma selected for this study were
not chosen for the concomitant presence of PIN. Perhaps surprising was
the frequent finding of scattered immunoreactive EBV cells in benign
glandular hyperplasia. These results suggest that EBV may play a role
in clearly proliferative but not necessarily malignant or premalignant
lesions. In this context, our findings in the prostate parallel the
above-described findings in nonprecancerous epithelial proliferations
of the breast and colon. Conversely, the presence of EBV in dysplastic
and precancerous proliferations of the prostate and breast underscores
that EBV may indeed have an optional role in the development of
carcinomas of these sites."
Detection of human polyomaviruses and papillomaviruses in prostatic
tissue reveals the prostate as a habitat for multiple viral infections.
A Zambrano, M Kalantari, A Simoneau, JL Jensen, LP Villareal. Prostate
2002 Dec 1;53(4):263-276. "The paraffin-embedded archival samples gave
variable, unsatisfactory results. Results from the fresh frozen
samples, however, were consistent and were frequently positive for JCV
and less frequent for BK virus DNA. ISH confirmed the presence of JCV
DNA in prostatic glandular epithelium."
Association between the presence of bacterial 16S RNA in prostate
specimens taken during transurethral resection of prostate and
subsequent risk of prostate cancer (Sweden). O Alexeyev, J Bergh, I
Marklund, C Thellenberg-Karlsson, F Wiklund, H Gronberg, A Bergh, F
Elgh. Cancer Causes Control 2006 Nov;17(9):1127-1133. 352 patients with
benign prostate hyperplasia (BPH) who later developed prostate cancer
(n = 171) and matched controls that did not progress to cancer (n =
181). "In 96/352 (27%) of the prostate tissue specimens 16S RNA were
detected. Sequence analysis revealed Propionibacterium acnes as the
predominant microorganism (23% of 16S RNA positive patients). The
second most frequent isolate-Escherichia coli was found in 12 (12%)
patients. The other isolates included Pseudomonas sp. (3 patients),
Actinomyces sp. (2), Streptococcus mutans (1), Corynebacterium sp. (2),
Nocardioides sp. (1), Rhodococcus sp. (1) Veillonella sp. (2). In P.
acnes positive samples 62% exhibited severe histological inflammation
versus 50% in the bacteria-negative group (p = 0.602). The presence of
P. acnes in the prostate was associated with prostate cancer
development (OR 2.17, 95% CI 0.77-6.95)."
Human papillomavirus and Epstein Barr virus in prostate cancer:
Koilocytes indicate potential oncogenic influences of human
papillomavirus in prostate cancer. NJ Whitaker, WK Glenn, A Sahrudin,
MM Orde, W Delprado, JS Lawson. Prostate 2013 Feb 15;73(3):236-241.
"Both HPV type 18 and EBV gene sequences were identified in a high and
approximately equal proportion of normal, benign, and prostate cancer
specimens. These sequences were located in the nuclei of prostate
epithelial cells. HPV associated koilocytes were identified in 24% of
prostate cancer specimens."
Evidence supporting the association of polyomavirus BK genome with prostate cancer. S Delbue, DV Matei, C Carloni, V Pecchenini, S Carluccio, S Villani, V Tringali, A Brescia, P Ferrante. Med Microbiol Immunol 2013 Jul 3 [Epub ahead of print]. 124 consecutive patients, 56 with PCA and 68 with benign prostatic hyperplasia (BPH). "BKV-positive tissue specimens were found in 32.1 and 22.1 % of PCA and BPH patients, respectively; in PCA group the number of positive BKV specimens/patients was significantly higher than in BPH group (3.06 vs. 1.73, p = 0.02). JCV genome was found in the biopsies collected from 28.1 and 24.2 % of PCA and BPH patients, respectively, with no significant difference in the rate of JCV specimens/patients between PCA and BPH groups."Delbue - Med Microbiol Immunol 2013 abstract / PubMed
Adenoviral E1B55K oncoprotein sequesters candidate leukemia
suppressor sequence-specific single-stranded DNA-binding protein 2 into
aggresomes. HB Fleisig, NI Orazio, H Liang, AF Tyler, HP Adams, MD
Weitzman, L Nagarajan. Oncogene 2007 Jul 19;26(33):4797-4805.
"Sequence-specific single-stranded DNA-binding protein 2 (SSBP2) is a
candidate tumor suppressor for human acute myelogenous leukemia (AML).
Inducible expression of SSBP2 causes growth arrest and partial
differentiation in AML cells. Here, we report that the adenoviral
oncoprotein E1B55K directly binds to endogenous SSBP2 protein and
sequesters it into juxtanuclear bodies in adenovirally transformed
human embryonic kidney (HEK) 293 cells... These data demonstrate that
E1B55K targets the candidate leukemia suppressor SSBP2 and suggest that
subverting its function may contribute to cell transformation by viral
ssDNA-binding protein 2 is frequently hypermethylated and suppresses
cell growth in human prostate cancer. JW Liu, JK Nagpal, W Sun, J Lee,
MS Kim, KL Ostrow, S Zhou, C Jeronimo, R Henrique, W Van Criekinge, CS
Moon, JA Califano, B Trink, D Sidransky. Clin Cancer Res 2008 Jun
15;14(12):3754-3760. "Quantitative methylation-specific PCR results
showed that the SSBP2 promoter was hypermethylated in 54 of 88 (61.4%)
primary prostate cancers versus 0 of 23 (0%) in benign prostatic
hyperplasia using a cutoff value of 120. Furthermore, we found that
expression of SSBP2 was down-regulated in primary prostate cancers and
cancer cell lines. Hypermethylation of the SSBP2 promoter and its
expression were closely associated with higher stages of prostate
Identification of a Novel Gammaretrovirus in Prostate Tumors of
Patients Homozygous for R462Q RNASEL Variant. A Urisman, RJ Molinaro, N
Fischer, SJ Plummer, G Casey, EA Klein, K Malathi, C Magi-Galluzzi, RR
Tubbs, D Ganem, RH Silverman, JL DeRisi. PLoS Pathog 2006 March; 2(3):
e25. A subset of patients with familial prostate cancer have a gene
defect which is associated with increased susceptibility to certain
infections. A high proportion of these patients have been infected with
a retrovirus, named XMRV, which is similar to murine leukemia viruses
(8/20 vs. 1/66). The Env protein sequence had the highest amino acid
identity with the Env protein of an infectious MuLV isolated from a
human small cell lung cancer line.
Integration site preference of xenotropic murine leukemia
virus-related virus, a new human retrovirus associated with prostate
cancer. S Kim, N Kim, B Dong, D Boren, SA Lee, J Das Gupta, C Gaughan,
EA Klein, C Lee, RH Silverman, SA Chow. J Virol 2008
Oct;82(20):9964-9977. "Balanced chromosome rearrangements, particularly
translocations, are strongly associated with distinct tumor entities
and may represent an initial event in oncogenesis. The common fragile
site is another cancer-associated genomic feature that is frequently
altered in non-virus-associated tumors. Both cancer breakpoints and
common fragile sites are preferential integration targets for vector
DNA, hepatitis B virus, and various DNA viruses, including human
papillomavirus, Epstein-Barr virus, simian virus 40, and
adeno-associated virus. These integration events may contribute
significantly to the development of various types of cancers by
disrupting the normal activity of tumor suppressor genes or
proto-oncogenes in the vicinity. In the SCID-X1 gene-therapy trial
wherein two patients received an MLV-derived vector and subsequently
developed leukemia via activation of the LMO2 oncogene, the two
integration sites targeted by the MLV-based vector reside within
FRA11E, a common fragile site known to correlate with chromosomal
breakpoints in tumors. Since XMRV integration in DU145 cells does not
display a bias for cancer breakpoints and common fragile sites, the
high XMRV integration preference seen in tumor samples for genomic
regions with the highest frequencies of cancer breakpoints and common
fragile sites is striking and likely represents a selection process.
The key question of whether these integrated proviruses are an indirect
consequence of genomic instability initiated by other genetic lesions
or perhaps have a direct role in prostate carcinogenesis awaits further
investigations." Integration also occurs in cytoband 16q22.1. "Two
other integration sites, one each located in 11q13.4 and 19p13.2, are
also in regions where high rates of chromosomal alterations have been
observed in breast and prostate cancers."
Prevalence of human gammaretrovirus XMRV in sporadic prostate
cancer. N Fischer, O Hellwinkel, C Schulz, FK Chun, H Huland, M
Aepfelbacher, T Schlomm. J Clin Virol 2008 Nov;43(3):277-283. "Forty
percent (8/20) of familial prostate cancer patients homozygous for a
mutation in RNase L (R462Q) were positive for XMRV, while the virus was
rarely (1/66) detected in familial prostate cancer patients
heterozygous for R462Q or carrying the wild type allele...
XMRV-specific sequences were detected in one of 105 tissue samples from
non-familial prostate cancer patients and from one of 70 tissue samples
from men without prostate cancer. The two XMRV-positive patients were
wild type or heterozygous for the R462Q mutation and thus carried at
least one fully functional RNase L allele."
XMRV is present in malignant prostatic epithelium and is associated
with prostate cancer, especially high-grade tumors. R Schlaberg, DJ
Choe, KR Brown, HM Thaker, IR Singh. Proc Natl Acad Sci U S A 2009 Sep
22;106(38):16351-16356. By quantitative PCR assay and
immunohistochemistry (IHC) with an anti-XMRV specific antiserum, XMRV
DNA was found in 6% and XMRV protein expression in 23% of 334
consecutive prostate cancers. There was no relation with a common
polymorphism in the RNASEL gene.
Lack of evidence for xenotropic murine leukemia virus-related virus
(XMRV) in German prostate cancer patients. O Hohn, H Krause, P
Barbarotto, L Niederstadt, N Beimforde, J Denner, K Miller, R Kurth, N
Bannert. Retrovirology 2009 Oct 16;6:92. 589 prostate tumor samples
were all negative for XMRV, either DNA or RNA.
The prostate cancer-associated human retrovirus XMRV lacks direct
transforming activity but can induce low rates of transformation in
cultured cells. MJ Metzger, CJ Holguin, R Mendoza, AD Miller. J Virol
2010 Feb;84(4):1874-1880. "Here we have used cultured fibroblast and
epithelial cell lines to test the hypothesis that XMRV might have
direct transforming activity but found only rare transformation events
suggestive of indirect transformation, even when the target cells
expressed the human Xpr1 cell-entry receptor for XMRV."
Detection of xenotropic murine leukemia virus-related virus in
normal and tumor tissue of patients from the southern United States
with prostate cancer is dependent on specific polymerase chain reaction
conditions. BP Danielson, GE Ayala, JT Kimata. J Infect Dis 2010 Nov
15;202(10):1470-1477. "XMRV was detected in 32 (22%) of the 144
patients. Patients were significantly more likely to test positive for
XMRV in both tumor and normal tissue rather than either alone (κ =
0.64). A positive result for XMRV was not significantly correlated with
the R462Q polymorphism (P = .82) or clinical pathological parameters of
prostate cancer, including Gleason score (P = .29)."
Prevalence of human xenotropic murine leukemia virus-related
gammaretrovirus (XMRV) in dutch prostate cancer patients. GW Verhaegh,
AS de Jong, FP Smit, SA Jannink, WJ Melchers, JA Schalken. Prostate
2011 Mar 1;71(4):415-420. XMRV sequences were detected in 3
out of 74 (4%) prostate cancer specimens. "The number of XMRV
containing cells was extremely low (1 in 600-7,000 cells). This was
corroborated by the fact that XMRV could not be detected in consecutive
tissue sections of the initial XMRV-positive cases."